Morpholine derivatives and their use as antagonists of tachikinins

ABSTRACT

The present invention relates to compounds of formula (I): wherein X is N or CH; and pharmaceutically acceptable salts and prodrugs thereof. The compounds are of p articular use in the treatment of pain, inflammation, migraine and emesis. ##STR1##

This application is a 371 of PCT/GB95/00983 filed May 1, 1995.

This invention relates to novel compounds which are useful as tachykininantagonists, particularly as antagonists of substance P. Moreparticularly, the invention relates to morpholine derivatives, processesfor their preparation, pharmaceutical compositions containing them, andtheir use in medicine.

The tachykinins are a group of naturally occurring peptides found widelydistributed throughout mammalian tissues, both within the centralnervous system and in peripheral nervous and circulatory systems.

At present, there are three known mammalian tachykinins referred to assubstance P, neurokinin A (NKA, substance K, neuromedin L) andneurokinin B (NKB, neuromedin K) (for review see J. E. Maggio, Peptides(1985) 6(suppl. 3), 237-242). The current nomenclature designates thethree tachykinin receptors mediating the biological actions of substanceP, NKA and NKB as the NK₁, NK₂ and NK₃ receptors, respectively.

Evidence for the usefulness of tachykinin receptor antagonists in pain,headache, especially migraine, Alzheimer's disease, multiple sclerosis,attenuation of morphine withdrawal, cardiovascular changes, oedema, suchas oedema caused by thermal injury, chronic inflammatory diseases suchas rheumatoid arthritis, asthma/bronchial hyperreactivity and otherrespiratory diseases including allergic rhinitis, inflammatory diseasesof the gut including ulcerative colitis and Crohn's disease, ocularinjury and ocular inflammatory diseases, proliferativevitreoretinopathy, irritable bowel syndrome and disorders of bladderfunction including cystitis and bladder detruser hyper-reflexia isreviewed in "Tachykinin Receptors and Tachykinin Receptor Antagonists",C. A. Maggi, R. Patacchini, P. Rovero and A. Giachetti, J. Auton.Pharmacol. (1993) 13, 23-93.

For instance, substance P is believed inter alia to be involved in theneurotransmission of pain sensations Otsuka et al, "Role of Substance Pas a Sensory Transmitter in Spinal Cord and Sympathetic Ganglia" in 1982Substance P in the Nervous System, Ciba Foundation Synmposium 91, 13-34(published by Pitman) and Otsuka and Yanagisawa, "Does Substance P Actas a Pain Transmitter?" TIPS (1987) 8, 506-510!, specifically in thetransmission of pain in migraine (B. E. B. Sandberg et al, J. Med. Chem,(1982) 25, 1009) and in arthritis Levine et al in Science (1984) 226,547-549!. Tachykinins have also been implicated in gastrointestinal (GI)disorders and diseases of the GI tract such as inflammatory boweldisease Mantyh et al in Neuroscience (1988) 25(3), 817-37 and D. Regoliin "Trends in Cluster Headache" Ed. Sicuteri et al Elsevier ScientificPublishers, Amsterdam (1987) page 85)! and emesis F. D. Tattersall etal, Eur. J. Pharmacol., (1993) 250, R5-R6!. It is also hypothesised thatthere is a neurogenic mechanism for arthritis in which substance P mayplay a role Kidd et al "A Neurogenic Mechanism for SymmetricalArthritis" in The Lancet, 11 Nov. 1989 and Gronblad et al,"Neuropeptides in Synovium of Patients with Rheumatoid Arthritis andOsteoarthritis" in J. Rheumatol. (1988) 15(12), 1807-10!. Therefore,substance P is believed to be involved in the inflammatory response indiseases such as rheumatoid arthritis and osteoarthritis, and fibrositisO'Byrne et al, Arthritis and Rheumatism (1990) 33, 1023-8!. Otherdisease areas where tachykinin antagonists are believed to be useful areallergic conditions Hamelet et al, Can. J. Pharmacol. Physiol. (1988)66, 1361-7!, immunoregulation Lotz et al, Science (1988) 241, 1218-21and Kimball et al, J. Immunol. (1988) 141(10), 3564-9! vasodilation,bronchospasm, reflex or neuronal control of the viscera Mantyh et al,Proc. Natl. Acad. Sci., USA (1988) 85, 3235-9! and, possibly byarresting or slowing β-amyloid-mediated neurodegenerative changesYankner et al, Science (1990) 250, 279-82! in senile dementia of theAlzheimer type, Alzheimer's disease and Down's Syndrome.

Tachykinin antagonists may also be useful in the treatment of small cellcarcinomas, in particular small cell lung cancer (SCLC) Langdon et al,Cancer Research (1992) 52, 4554-7!.

Substance P may also play a role in demyelinating diseases such asmultiple sclerosis and amyotrophic lateral sclerosis J. Luber-Narod etal, poster C.I.N.P. XVIIIth Congress, 28th Jun.-2nd Jul. 1992!, and indisorders of bladder function such as bladder detrusor hyper-reflexia(The Lancet, 16th May 1992, 1239).

It has furthermore been suggested that tachykinins have utility in thefollowing disorders: depression, dysthymic disorders, chronicobstructive airways disease, hypersensitivity disorders such as poisonivy, vasospastic diseases such as angina and Reynauld's disease,fibrosing and collagen diseases such as scleroderma and eosinophilicfascioliasis, reflex sympathetic dystrophy such as shoulder/handsyndrome, addiction disorders such as alcoholism, stress related somaticdisorders, neuropathy, neuralgia, disorders related to immuneenhancement or suppression such as systemic lupus erythmatosus (Europeanpatent specification no. 0 436 334), ophthalmic disease such asconjuctivitis, vernal conjunctivitis, and the like, and cutaneousdiseases such as contact dermatitis, atopic dermatitis, urticaria, andother eczematoid dermatitis (European patent specification no. 0 394989).

European patent specification no. 0 577 394 (published 5th Jan. 1994)discloses morpholine and thiomorpholine tachykinin receptor antagonistsof the general formula ##STR2## wherein R¹ is a large variety ofsubstituents;

R² and R³ are inter alia hydrogen;

R⁴ is inter alia ##STR3## R⁵ is inter alia optionally substitutedphenyl; R⁶, R⁷ and R⁸ are a variety of substituents;

X is O, S, SO or SO₂ ;

Y is inter alia O; and

Z is hydrogen or C₁₋₄ alkyl.

We have found the compounds of the present invention to be particularlypotent and useful antagonists of tachykinins, especially of substance P.

It is desirable that compounds may be administered orally and byinjection. Certain compounds have now been discovered which act aspotent non-peptide tachykinin antagonists and which, by virtue of theiradvantageous aqueous solubility, are particularly easily formulated foradministration by both the oral and injection routes, for example, inaqueous media.

The present invention provides compounds which have the formula (I):##STR4## where X is N or CH;

and pharmaceutically acceptable salts and prodrugs thereof

For use in medicine, the salts of the compounds of formula (I) will benon-toxic pharmaceutically acceptable salts. Other salts may, however,be useful in the preparation of the compounds according to the inventionor of their non-toxic pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds of this inventioninclude acid addition salts which may, for example, be formed by mixinga solution of a compound according to the invention with a solution of apharmaceutically acceptable acid such as hydrochloric acid, fumaricacid, p-toluenesulphonic acid, maleic acid, succinic acid, acetic acid,citric acid, tartaric acid, carbonic acid or phosphoric acid. Salts ofamine groups may also comprise quaternary ammonium salts in which theamino nitrogen atom carries a suitable organic group such as an alkyl,alkenyl, alkynyl or aralkyl moiety.

The compounds according to the invention have three asymmetric centres,and may accordingly exist both as enantiomers and as diastereoisomers.It is to be understood that all such isomers and mixtures thereof areencompassed within the scope of the present invention.

The preferred compounds of formula (I) will have the 2- and3-substituent cis and the preferred stereochemistry at the 2-position isthat possessed by the compounds of Examples 1 and 2 (i.e. 2-(R)-), thepreferred stereochemistry of the 3-position is that possessed by thecompounds of Examples 1 and 2 (i.e. 3-(S)), and the stereochemistry ofthe carbon to which the α-methyl group is attached is preferably (R),i.e. compounds of the formula (Ia): ##STR5##

The present invention includes within its scope prodrugs of thecompounds of formula (I) above. In general, such prodrugs will befunctional derivatives of the compounds of formula (I) which are readilyconvertible in vivo into the required compounds of formula (I).Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in "Design of Prodrugs",ed. H. Bundgaard, Elsevier, 1985.

A prodrug may be a pharmacologically inactive derivative of abiologically active substance (the "parent drug" or "parent molecule")that requires transformation within the body in order to release theactive drug, and that has improved delivery properties over the parentdrug molecule. The transformation in vivo may be, for example, as theresult of some metabolic process, such as chemical or enzymatichydrolysis of a carboxylic, phosphoric or sulphate ester, or reductionor oxidation of a susceptible functionality.

Thus, for example, certain preferred prodrugs may not be antagonists oftachykinin, particularly substance P, activity to any significant extent(or not at all). Such compounds, however, are still advantageous intreating the various conditions described herein, especially where aninjectable formulation is preferred.

The advantages of a prodrug may lie in its physical properties, such asenhanced water solubility for parenteral administration compared withthe parent drug, or it may enhance absorption from the digestive tract,or it may enhance drug stability for long-term storage. Ideally aprodrug will improve the overall efficacy of a parent drug, for example,through the reduction of toxicity and unwanted effects of drugs bycontrolling their absorption, blood levels, metabolism, distribution andcellular uptake.

It will be appreciated that in the compounds of formula (I) above, the1,2,4-triazol-3-yl or 1,3-imidazol-4-yl group may be derivatized to givea prodrug of the compounds of the present invention.

Suitable prodrug derivatives include:

(a) --(CHR¹⁰)_(n) --PO(OH)O⁻.M⁺ ;

(b) --(CHR¹⁰)_(n) --PO(O⁻)₂.2M⁺ ;

(c) --(CHR¹⁰)_(n) --PO(O⁻)₂.D²⁺ ;

(d) --(CHR¹⁰)_(n) --SO₃ ⁻.M⁺ ;

(e) --COCH₂ CH₂ CO₂ ⁻.M⁺ ;

(f) --COH;

(g) --CO(CH₂)_(n) N(R¹⁰)₂ ; and

(h) --(CH(R¹⁰)O)_(n) --COR¹¹,

wherein

n is zero or 1;

M⁺ is a pharmaceutically acceptable monovalent counterion;

D²⁺ is a pharmaceutically acceptable divalent counterion;

R¹⁰ is hydrogen or C₁₋₃ alkyl; and

R¹¹ is a group selected from --O(CH₂)₂ NH₃ ⁺.M⁻ ;

--O(CH₂)₂ NH₂ (R¹²)⁺.M³¹ ; --OCH₂ CO₂ ⁻.M⁺ ;

--OCH(CO₂ ⁻.M⁺)CH₂ CO₂ ⁻.M⁺ ; --OCH₂ CH(NH₃ ⁺)CO₂ ⁻ ;

--OC(CO₂ ⁻.M⁺)(CH₂ CO₂ ⁻.M⁺)₂ ; and ##STR6## in which M⁻ is apharmaceutically acceptable monovalent counterion, and R¹² is hydrogen,C₁₋₄ alkyl or C₂₋₄ alkyl substituted by a hydroxyl or C₁₋₄ alkoxy group.

Particularly preferred prodrug derivatives are:

(a) --(CHR¹⁰)_(n) --PO(OH)O⁻.M⁺ ;

(b) --(CHR¹⁰)_(n) --PO(O⁻)₂.2M⁺ ;

(c) --(CHR¹⁰)_(n) --PO(O⁻)₂.D²⁺ ; especially where n is zero.

The term "parent molecule", "parent compound" or "parent drug" refers tothe biologically active entity that is released via enzymatic action ofa metabolic or catabolic process, or via a chemical process followingadministration of the prodrug. The parent compound may also be thestarting material for the preparation of its corresponding prodrug.

While all of the usual routes of administration are useful with theabove prodrugs, the preferred routes of administration are oral andintravenous. After gastrointestinal absorption or intravenousadministration, the prodrugs are hydrolyzed or otherwise cleaved in vivoto the corresponding parent compound of formula (I), or apharmaceutically acceptable salt thereof.

Examples of negative monovalent counterions defined herein as "M⁻ "include acetate, adipate, benzoate, benzenesulfonate, bisulfate,butyrate, camphorate, camphorsulfonate, citrate, ethanesulfonate,fumarate, hemisulfate, 2-hydroxyethylsulfonate, heptanoate, hexanoate,hydrochloride, hydrobromide, hydroiodide, lactate, malate, maleate,methanesulfonate, 2-naphthalenesulfonate, oxalate, pamoate, persulfate,picrate, pivalate, propionate, salicylate, stearate, succinate, sulfate,tartrate, tosylate (p-toluenesulfonate), and undecanoate.

Base salts (which are pharmaceutically acceptable monovalent cationsdefined herein as "M⁺ " or pharmaceutically acceptable divalent cationsdefined herein as "D²⁺ ", if appropriate) include ammonium salts, alkalimetal salts such as sodium, lithium and potassium salts, alkaline earthmetal salts such as aluminium, calcium and magnesium salts, salts withorganic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, andsalts with amino acids such as arginine, lysine, ornithine, and soforth. If M⁺ is a monovalent cation, it is recognised that if thedefinition 2M⁺ is present, each of M⁺ may be the same or different. Inaddition, it is similarly recognised that if the definition 2M⁺ ispresent, a divalent cation D²⁺ may instead be present. Also, the basicnitrogen-containing groups may be quaternized with such agents as: loweralkyl halides, such as methyl, ethyl, propyl, and butyl chlorides,bromides and iodides; dialkyl sulfates like dimethyl, diethyl anddibutyl; diamyl sulfates; long chain halides such as decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides; aralkyl halideslike benzyl bromide and others. The non-toxic physiologically acceptablesalts are preferred, although other salts are also useful, such as inisolating or purifying the product.

The salts may be formed by conventional means, such as by reacting thefree base form of the product with one or more equivalents of theappropriate acid in a solvent or medium in which the salt is insoluble,or in a solvent such as water which is removed in vacuo or by freezedrying or by exchanging the anions of an existing salt for another anionon a suitable ion exchange resin.

The present invention includes within its scope solvates of thecompounds of formula (I) and salts thereof, for example, hydrates.

The present invention further provides pharmaceutical compositionscomprising a compound of formula (I) in association with apharmaceutically acceptable carrier or excipient.

Preferably the compositions according to the invention are in unitdosage forms such as tablets, pills, capsules, powders, granules,solutions or suspensions, or suppositories, for oral, parenteral orrectal administration, or administration by inhalation or insufflation.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical carrier, e.g. conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents, e.g. water, to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention, or a non-toxic pharmaceuticallyacceptable salt thereof. When referring to these preformulationcompositions as homogeneous, it is meant that the active ingredient isdispersed evenly throughout the composition so that the composition maybe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules. This solid preformulation composition isthen subdivided into unit dosage forms of the type described abovecontaining from 0.1 to about 500 mg of the active ingredient of thepresent invention.

The tablets or pills of the novel composition can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permits theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

Preferred compositions for administration by injection include thosecomprising a compound of formula (I), as the active ingredient, inassociation with a surface-active agent (or wetting agent or surfactant)or in the form of an emulsion (as a water-in-oil or oil-in-wateremulsion).

Suitable surface-active agents include, in particular, non-ionic agents,such as polyoxyethylenesorbitans (e.g. Tween™ 20, 40, 60, 80 or 85) andother sorbitans (e.g. Span™ 20, 40, 60, 80 or 85). Compositions with asurface-active agent will conveniently comprise between 0.05 and 5%surface-active agent, and preferably between 0.1 and 2.5%. It will beappreciated that other ingredients may be added, for example mannitol orother pharmaceutically acceptable vehicles, if necessary.

Suitable emulsions may be prepared using commercially available fatemulsions, such as Intralipid™, Liposyn™, Infonutrol™, Lipofundin™ andLipiphysan™. The active ingredient may be either dissolved in apre-mixed emulsion composition or alternatively it may be dissolved inan oil (e.g. soybean oil, safflower oil, cottonseed oil, sesame oil,corn oil or almond oil) and an emulsion formed upon mixing with aphospholipid (e.g. egg phospholipids, soybean phospholipids or soybeanlecithin) and water. It will be appreciated that other ingredients maybe added, for example gylcerol or glucose, to adjust the tonicity of theemulsion. Suitable emulsions will typically contain up to 20% oil, forexample, between 5 and 20%. The fat emulsion will preferably comprisefat droplets between 0.1 and 1.0 μm, particularly 0.1 and 0.5 μm, andhave a pH in the range of 5.5 to 8.0.

Particularly preferred emulsion compositions are those prepared bymixing a compound of formula (I) with Intralipid™ or the componentsthereof (soybean oil, egg phospholipids, glycerol and water).

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as set outabove. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably sterile pharmaceutically acceptable solvents may be nebulisedby use of inert gases. Nebulised solutions may be breathed directly fromthe nebulising device or the nebulising device may be attached to a facemask, tent or intermittent positive pressure breathing machine.Solution, suspension or powder compositions may be administered,preferably orally or nasally, from devices which deliver the formulationin an appropriate manner.

The present invention further provides a process for the preparation ofa pharmaceutical composition comprising a compound of formula (I), whichprocess comprises bringing a compound of formula (I) into associationwith a pharmaceutically acceptable carrier or excipient.

The compounds of formula (I) are of value in the treatment of a widevariety of clinical conditions which are characterised by the presenceof an excess of tachykinin, in particular substance P, activity.

These may include disorders of the central nervous system such asanxiety, depression, psychosis and schizophrenia; epilepsy;neurodegenerative disorders such as dementia, including AIDS relateddementia, senile dementia of the Alzheimer type, Alzheimer's disease andDown's syndrome; demyelinating diseases such as multiple sclerosis (MS)and amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease) and otherneuropathological disorders such as peripheral neuropathy, for exampleAIDS related neuropathy, diabetic and chemotherapy-induced neuropathy,and postherpetic and other neuralgias; neuronal damage, such ascerebralischemic damage and cerebral edema in cerebrovascular disorders;small cell carcinomas such as small cell lung cancer; respiratorydiseases, particularly those associated with excess mucus secretion suchas chronic obstructive airways disease, bronchopneumonia, chronicbronchitis, asthma, and bronchospasm; airways diseases modulated byneurogenic inflammation; diseases characterised by neurogenic mucussecretion, such as cystic fibrosis; diseases associated with decreasedglandular secretions, including lacrimation, such as Sjogren's syndrome,hyperlipoproteinemias IV and V, hemocromatosis, sarcoidosis, andamyloidosis; inflammatory diseases such as inflammatory bowel disease,psoriasis, fibrositis, ocular inflammation, osteoarthritis, rheumatoidarthritis, pruritis and sunburn; allergies such as eczema and rhinitis;hypersensitivity disorders such as poison ivy; ophthalmic diseases suchas conjunctivitis, vernal conjunctivitis, dry eye syndrome, and thelike; ophthalmic conditions associated with cell proliferation such asproliferative vitreoretinopathy; cutaneous diseases such as contactdermatitis, atopic dermatitis, urticaria, and other eczematoiddermatitis; addiction disorders including the withdrawal responseproduced by chronic treatment with, or abuse of, drugs such asbenzodiazepines, opiates, cocaine, alcohol and nicotine; stress relatedsomatic disorders; reflex sympathetic dystrophy such as shoulder/handsyndrome; dysthymic disorders; adverse immunological reactions such asrejection of transplanted tissues and disorders related to immuneenhancement or suppression such as systemic lupus erythematosus;gastrointestinal (GI) disorders and diseases of the GI tract such asdisorders associated with the neuronal control of viscera, ulcerativecolitis, Crohn's disease, irritable bowel syndrome and emesis, includingacute, delayed, post-operative, late phase or anticipatory emesis suchas emesis induced by chemotherapy, radiation, toxins, viral or bacterialinfections, pregnancy, vestibular disorders, motion, surgery, migraine,opioid analgesics, and variations in intercranial pressure, inparticular, for example, drug or radiation induced emesis orpost-operative nausea and vomiting; disorders of bladder function suchas cystitis, bladder detrusor hyper-reflexia and incontinence; fibrosingand collagen diseases such as scleroderma and eosinophilic fascioliasis;disorders of blood flow caused by vasodilation and vasospastic diseasessuch as angina, migraine and Reynaud's disease; and pain or nociception,for example, that attributable to or associated with any of theforegoing conditions, especially the transmission of pain in migraine.

Hence, the compounds of the present invention may be of use in thetreatment of physiological disorders associated with excessivestimulation of tachykinin receptors, especially neurokinin-1 receptors,and as neurokinin-1 antagonists for the control and/or treatment of anyof the aforementioned clinical conditions in mammals, including humans.

The compounds of formula (I) are also of value in the treatment of acombination of the above conditions, in particular in the treatment ofcombined post-operative pain and post-operative nausea and vomiting.

The compounds of formula (I) are particularly useful in the treatment ofemesis, including acute, delayed, post-operative, late phase oranticipatory emesis, such as emesis or nausea induced by chemotherapy,radiation, toxins, such as metabolic or microbial toxins, viral orbacterial infections, pregnancy, vestibular disorders, motion,mechanical stimulation, gastrointestinal obstruction, reducedgatrointestinal motility, visceral pain, psychological stress ordisturbance, high altitude, weightlessness, opioid analgesics,intoxication, resulting for example from consumption of alcohol,surgery, migraine, and variations in intercranial pressure. Mostespecially, the compounds of formula (I) are of use in the treatment ofemesis induced by antineoplastic (cytotonic) agents including thoseroutinely used in cancer chemotherapy.

Examples of such chemotherapeutic agents include alkylating agents, forexample, nitrogen mustards, ethyleneimine compounds, alkyl sulphonatesand other compounds with an alkylating action such as nitrosoureas,cisplatin and dacarbazine; antimetabolites, for example, folic acid,purine or pyrimidine antagonists; mitotic inhibitors, for example, vincaalkaloids and derivatives of podophyllotoxin; and cytotoxic antibiotics.

Particular examples of chemotherapeutic agents are described, forinstance, by D. J. Stewart in "Nausea and Vomiting: Recent Research andClinical Advances", Eds. J. Kuucharczyk et al, CRC Press Inc., BocaRaton, Fla., USA (1991) pages 177-203, especially page 188. Commonlyused chemotherapeutic agents include cisplatin, dacarbazine (DTIC),dactinomycin, mechlorethamine (nitrogen mustard), streptozocin,cyclophosphamide, carmustine (BCNU), lomustine (CCNU), doxorubicin(adriamycin), daunorubicin, procarbazine, mitomycin, cytarabine,etoposide, methotrexate, 5-fluorouracil, vinblastine, vincristine,bleomycin and chlorambucil R. J. Gralla et al in Cancer TreatmentReports (1984) 68(1), 163-172!.

The compounds of formula (I) are also of use in the treatment of emesisinduced by radiation including radiation therapy such as in thetreatment of cancer, or radiation sickness; and in the treatment ofpost-operative nausea and vomiting.

It will be appreciated that the compounds of formula (I) may bepresented together with another therapeutic agent as a combinedpreparation for simultaneous, separate or sequential use for the reliefof emesis. Such combined preparations may be, for example, in the formof a twin pack.

A further aspect of the present invention comprises the compounds offormula (I) in combination with a 5-HT₃ antagonist, such as ondansetron,granisetron or tropisetron, or other anti-emetic medicaments, forexample, a dopamine antagonist such as metoclopramide or GABAB receptoragonists such as baclofen. Additionally, a compound of formula (I) maybe administered in combination with an anti-inflammatory corticosteroid,such as dexamethasone, triamcinolone, triamcinolone acetonide,flunisolide, budesonide, or others such as those disclosed in U.S. Pat.Nos. 2,789,118, 2,990,401, 3,048,581, 3,126,375, 3,929,768, 3,996,359,3,928,326 and 3,749,712. Dexamethasone (Decadron™) is particularlypreferred. Furthermore, a compound of formula (I) may be administered incombination with a chemotherapeutic agent such as an alkylating agent,antimetabolite, mitotic inhibitor or cytotoxic antibiotic, as describedabove. In general, the currently available dosage forms of the knowntherapeutic agents for use in such combinations will be suitable.

When tested in the ferret model of cisplatin-induced emesis described byF. D. Tattersall et al, in Eur. J. pharmacol., (1993) 250, R5-R6, thecompounds of the present invention were found to attenuate the retchingand vomiting induced by cisplatin.

The compounds of formula (I) are also particularly useful in thetreatment of pain or nociception and/or inflammation and disordersassociated therewith such as, for example, neuropathy, such as diabeticand chemotherapy-induced neuropathy, postherpetic and other neuralgias,asthma, osteroarthritis, rheumatoid arthritis, headache and especiallymigraine.

The present invention further provides a compound of formula (I) for usein therapy.

According to a further or alternative aspect, the present inventionprovides a compound of formula (I) for use in the manufacture of amedicament for the treatment of physiological disorders associated withan excess of tachykinins, especially substance P.

The present invention also provides a method for the treatment orprevention of physiological disorders associated with an excess oftachykinins, especially substance P, which method comprisesadministration to a patient in need thereof of a tachykinin reducingamount of a compound of formula (I) or a composition comprising acompound of formula (I).

For the treatment of certain conditions it may be desirable to employ acompound according to the present invention in conjunction with anotherpharmacologically active agent. For example, for the treatment ofrespiratory diseases such as asthma, a compound of formula (I) may beused in conjunction with a bronchodilator, such as a β₂ -adrenergicreceptor antagonist or tachykinin antagonist which acts at NK-2receptors. The compound of formula (I) and the bronchodilator may beadministered to a patient simultaneously, sequentially or incombination.

Likewise, a compound of the present invention may be employed with aleukotriene antagonists, such as a leukotriene D₄ antagonist such as acompound selected from those disclosed in European patent specificationnos. 0 480 717 and 0 604 114 and in U.S. Pat. Nos. 4,859,692 and5,270,324. This combination is particularly useful in the treatment ofrespiratory diseases such as asthma, chronic bronchitis and cough.

The present invention accordingly provides a method for the treatment ofa respiratory disease, such as asthma, which method comprisesadministration to a patient in need thereof of an effective amount of acompound of formula (I) and an effective amount of a bronchodilator.

The present invention also provides a composition comprising a compoundof formula (I), a bronchodilator, and a pharmaceutically acceptablecarrier.

It will be appreciated that for the treatment or prevention of migraine,a compound of the present invention may be used in conjunction withother anti-migraine agents, such as ergotamines or 5-HT₁ agonists,especially sumatriptan.

Likewise, for the treatment of behavioural hyperalgesia, a compound ofthe present invention may be used in conjunction with an antagonist ofN-methyl D-aspartate (NMDA), such as dizocilpine.

For the treatment or prevention of inflammatory conditions in the lowerurinary tract, especially cystitis, a compound of the present inventionmay be used in conjunction with an antiinflammatory agent such as abradykinin receptor antagonist.

In the treatment of the conditions associated with an excess oftachykinins, a suitable dosage level is about 0.001 to 50 mg/kg per day,in particular about 0.01 to about 25 mg/kg, such as from about 0.05 toabout 10 mg/kg per day.

For example, in the treatment of conditions involving theneurotransmission of pain sensations, a suitable dosage level is about0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day,and especially about 0.005 to 5 mg/kg per day. The compound may beadministered on a regimen of 1 to 4 times per day, preferably once ortwice per day.

In the treatment-of emesis using an injectable formulation, a suitabledosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005to 5 mg/kg per day, and especially 0.01 to 1 mg/kg per day. The compoundmay be administered on a regimen of 1 to 4 times per day, preferablyonce or twice per day.

It will be appreciated that the amount of the compound of formula (I)required for use in any treatment will vary not only with the particularcomposition selected but also with the route of administration, thenature of the condition being treated, and the age and condition of thepatient, and will ultimately be at the discretion of the attendantphysician.

According to a process (A), the compounds of the present invention maybe prepared from the compound of formula (II) ##STR7## by reaction witha compound of formula (III): ##STR8## or a protected derivative thereof,wherein X is N or CH, and L is a leaving group such as a halogen atom,for example, chlorine, bromine or iodine or an alkyl- orarylsulphonyloxy group, for example, a mesylate or tosylate group,followed where necessary by deprotection in a conventional manner.

One particularly suitable protecting group for the compounds of formula(III) is the p-toluenesulphonyl group.

This reaction may be performed in conventional manner, for example in anorganic solvent such as dimethylformamide in the presence of an acidacceptor such as potassium carbonate.

Alternatively, according to a process (B), the compound of formula (I)in which X is N may be prepared by reaction of an intermediate offormula (II) with a compound of formula (IV) ##STR9## wherein Hal is ahalogen atom, for example, bromine, chlorine or iodine, in the presenceof a base.

Suitable bases of use in the reaction include alkali metal carbonatessuch as, for example, potassium carbonate. The reaction is convenientlyeffected in an anhydrous organic solvent such as, for example, anhydrousdimethylformamide, preferably at elevated temperature, such as between60° C. and 140° C.

Further details of suitable procedures will be found in the accompanyingExamples.

Compounds of formula (III) are commercially available or may be preparedby the procedures described in the accompanying Examples or fromcommercially available compounds by methods readily apparent to oneskilled in the art.

Compounds of formula (IV) may be prepared as described in J. Med. Chem.,27, 849 (1984).

The compounds of the formula (II) may be prepared as shown in thefollowing Scheme: ##STR10##

The following references describe methods which may be applied by theskilled worker to the chemical synthesis set forth above once theskilled worker has read the disclosure herein.

(i) D. A. Evans et al., J. Am. Chem. Soc., 112, 4011 (1990).

(ii) Yanagisawa, I. et al., J. Med. Chem., 27 849 (1984).

(iii) Duschinsky, R. et al., J. Am. Chem. Soc., 70, 657 (1948).

(iv) Tebbe F. N. et al., J. Am. Chem. Soc., 100, 3611 (1978).

(v) Petasis, N. A. et al., J. Am. Chem. Soc., 112, 6532 (1990).

(vi) Takai, K. et al., J. Org. Chem., 52, 4412 (1987).

The Examples disclosed herein produce predominantly the preferredisomers. The unfavoured isomers are also produced as minor components.If desired they may be isolated and employed to prepare the variousstereoisomers in conventional manner, for example chromatography usingan appropriate chiral column. However, the skilled worker willappreciate that although the Examples have been optimized to theproduction of the preferred isomers, variation in solvent, reagents,chromatography etc can be readily employed to yield the other isomers.

L-Selectride is lithium tri-sec-butylborohydride.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

The compounds of the present invention were tested by the methods setout at pages 36 to 39 of International Patent Specification No. WO93/01165. The compounds were both found to be active with IC₅₀ at theNK1 receptor of 0.1 nM.

DESCRIPTION 1 (S)-(4-Fluorophenyl)glycine

Via Chiral Synthesis

Step A

3-(4-Fluorophenyl)acetyl-4-(S)-benzyl-2-oxazolidinone

An oven-dried, 1 L 3-necked flask, equipped with a septum, nitrogeninlet, thermometer, and a magnetic stirring bar, was flushed withnitrogen and charged with a solution of 5.09 g (33.0 mmol) of4-fluorophenylacetic acid in 100 ml of anhydrous ether. The solution wascooled to -10° C. and treated with 5.60 ml (40.0 mmol) of triethylaminefollowed by 4.30 ml (35.0 mmol) of trimethylacetyl chloride. A whiteprecipitate formed immediately. The resulting mixture was stirred at-10° C. for 40 minutes, then cooled to -78° C.

An oven-dried, 250 ml round bottom flask, equipped with a septum and amagnetic stirring bar, was flushed with nitrogen and charged with asolution of 5.31 g (30.0 mmol) of 4-(S)-benzyl-2-oxazolidinone in 40 mlof dry THF. The solution was stirred in a dry ice/acetone bath for 10minutes, then 18.8 ml of 1.6M n-butyllithium solution in hexanes wasslowly added. After 10 minutes, the lithiated oxazolidinone solution wasadded, via cannula, to the above mixture in the 3-necked flask. Thecooling bath was removed from the resulting mixture and the temperaturewas allowed to rise to 0° C. The reaction was quenched with 100 ml ofsaturated aqueous ammonium chloride solution, transferred to a 1 lflask, and the ether and THF were removed in vacuo. The concentratedmixture was partitioned between 300 ml of methylene chloride and 50 mlof water and the layers were separated. The organic layer was washedwith 100 ml of 2N aqueous hydrochloric acid solution, 300 ml ofsaturated aqueous sodium bicarbonate solution, dried over magnesiumsulfate and concentrated in vacuo. Flash chromatography on 400 g ofsilica gel using 3:2 v/v hexanes/ether as the eluant afforded 8.95 g ofan oil that slowly solidified on standing. Recrystallisation from 10:1hexanes/ether afforded 7.89 g (83%) of the title compound as a whitesolid: mp 64°-66° C. MS (FAB): m/z 314 (M⁺ +H, 100%), 177 (M-ArCH₂ CO+H,85%). ¹ H NMR (400 MHz, CDCl₃) δ2.76 (1H, dd, J=13.2, 9.2 Hz), 3.26 (dd,J=13.2, 3.2 Hz), 4.16-4.34 (4H, m), 4.65 (1H, m), 7.02-7.33 (9H, m).Analysis Calcd. for C₁₈ H₁₆ FNO₃ : C, 69.00; H, 5.15; N, 4.47; F, 6.06;Found: C, 68.86; H, 5.14; N, 4.48; F, 6.08%

Step B

3-((S)-Azido-(4-fluorophenyl))acetyl-4-(S)-benzyl-2-oxazolidinone

An oven-dried, 1 l 3-necked flask, equipped with a septum, nitrogeninlet, thermometer, and a magnetic stirring bar, was flushed withnitrogen and charged with a solution of 58.0 ml of 1M potassiumbis(trimethylsilyl)amide solution in toluene and 85 ml of THF and wascooled to -78° C. An oven-dried 250 ml round-bottomed flask, equippedwith a septum and a magnetic stirring bar, was flushed with nitrogen andcharged with a solution of 7.20 g (23.0 mmol) of3-(4-fluorophenyl)acetyl-4-(S)-benzyl-2-oxazolidinone (from Step A) in40 ml of THF. The acyl oxazolidinone solution was stirred in a dryice/acetone bath for 10 minutes, then transferred, via cannula, to thepotassium bis(trimethylsilyl)amide solution at such a rate that theinternal temperature of the mixture was maintained below -70° C. Theacyl oxazolidinone flask was rinsed with 15 ml of THF and the rinse wasadded, via cannula, to the reaction mixture and the resulting mixturewas stirred at -78° C. for 30 minutes. An oven-dried, 250 mlround-bottomed flask, equipped with a septum and a magnetic stirringbar, was flushed with nitrogen and charged with a solution of 10.89 g(35.0 mmol) of 2,4,6-triisopropylphenylsulfonyl azide in 40 ml of THF.The azide solution was stirred in a dry ice/acetone bath for 10 minutes,then transferred, via cannula, to the reaction mixture at such a ratethat the internal temperature of the mixture was maintained below -70°C. After 2 minutes, the reaction was quenched with 6.0 ml of glacialacetic acid, the cooling bath was removed and the mixture was stirred atroom temperature for 18 hours. The quenched reaction mixture waspartitioned between 300 ml of ethyl acetate and 300 ml of 50% saturatedaqueous sodium bicarbonate solution. The organic layer was separated,dried over magnesium sulfate, and concentrated in vacuo. Flashchromatography on 500 g of silica gel using 2:1 v/v, then 1:1 v/vhexanes/methylene chloride as the eluant afforded 5.45 g (67%) of thetitle compound as an oil. IR Spectrum (neat, cm⁻¹): 2104, 1781, 1702. ¹H NMR (400 MHz, CDCl₃) δ2.86 (1H, dd, J=13.2, 9.6 Hz), 3.40 (1H, dd,J=13.2, 3.2 Hz), 4.09-4.19 (2H, m), 4.62-4.68 (1H, m), 6.14 (1H, s),7.07-7.47 (9H, m). Analysis Calcd. for C₁₈ H₁₅ FN₄ O₃ :C 61.01; H, 4.27;N, 15.81; F, 5.36; Found: C, 60.99; H, 4.19; N, 15.80; F, 5.34%

Step C

(S)-Azido-(4-fluorophenyl)acetic acid

A solution of 5.40 g (15.2 mmol) of 3-((S)-azido-(4-fluorophenyl))acetyl-4-(S)-benzyl-2-oxazolidinone (from Step B) in 200 ml of 3:1 v/vTHF/water was stirred in an ice bath for 10 minutes. 1.28 g (30.4 mmol)of lithium hydroxide monohydrate was added in one portion and theresulting mixture was stirred cold for 30 minutes. The reaction mixturewas partitioned between 100 ml of methylene chloride and 100 ml of 25%saturated aqueous sodium bicarbonate solution and the layers wereseparated. The aqueous layer was washed with 2×100 ml of methylenechloride and acidified to pH 2 with 2N aqueous hydrochloric acidsolution.

The resulting mixture was extracted with 2×100 ml of ethyl acetate; theextracts were combined, washed with 50 ml of saturated aqueous sodiumchloride solution, dried over magnesium sulfate, and concentrated invacuo to afford 2.30 g (77%) of the title compound as an oil that wasused in the following step without further purification. IR Spectrum(neat, cm⁻¹): 2111, 1724. ¹ H NMR (400 MHz, CDCl₃) δ5.06 (1H, s),7.08-7.45 (4H, m), 8.75 (1H, br s).

Step D

(S)-(4-Fluorophenyl)glycine

A mixture of 2.30 g (1 1.8 mmol) of (S)-azido-(4-fluorophenyl)aceticacid (from Step C), 2.50 mg 10% palladium on carbon catalyst and 160 ml3:1 v/v water/acetic acid was stirred under an atmosphere of hydrogenfor 18 hours. The reaction mixture was filtered through Celite and theflask and filter cake were rinsed well with ˜1 l of 3:1 v/v water/aceticacid. The filtrate was concentrated in vacuo to about 50 ml of volume.300 ml of toluene was added and the mixture concentrated to afford asolid. The solid was suspended in 1:1 v/v methanol/ether, filtered anddried to afford 1.99 g (100%) of the title compound. ¹ H NMR (400 MHz,D₂ O+NaOD) δ3.97 (1H, s), 6.77 (2H, app t, J=8.8 Hz), 7.01 (2H, app t,J=5.6 Hz).

Via Resolution:

Step A'

(4-Fluorophenyl)acetyl chloride

A solution of 150 g (0.974 mol) of 4-(fluorophenyl)acetic acid and 1 mlof N,N-dimethylformamide in 500 ml of toluene at 40° C. was treated with20 ml of thionyl chloride and heated to 40° C. An additional 61.2 ml ofthionyl chloride was added dropwise over 1.5 hours. After the addition,the solution was heated at 50° C. for 1 hour, the solvent was removed invacuo and the residual oil was distilled at reduced pressure (1.5 mmHg)to afford 150.4 g (89.5%) of the title compound, bp=68°-70° C.

Step B'

Methyl 2-bromo-3-(4-fluorophenyl)acetate

A mixture of 150.4 g (0.872 mol) of 4-(fluorophenyl)acetyl chloride(from Step A') and 174.5 g (1.09 mol) of bromine was irradiated at40°-50° C. with a quartz lamp for 5 hours. The reaction mixture wasadded dropwise to 400 ml of methanol and the solution was stirred for 16hours. The solvent was removed in vacuo and the residual oil wasdistilled at reduced pressure (1.5 mmHg) to afford 198.5 g (92%) of thetitle compound, bp=106°-110° C.

Step C'

Methyl (±)-(4-fluorophenyl)glycine

A solution of 24.7 g (0.1 mol) of methyl 2-bromo-2-(4-fluorophenyl)acetate (from Step B') and 2.28 g (0.01 mol) of benzyl triethylammoniumchloride in 25 ml of methanol was treated with 6.8 g (0.105 mol) ofsodium azide and the resulting mixture was stirred for 20 hours at roomtemperature. The reaction mixture was filtered; the filtrate was dilutedwith 50 ml of methanol and hydrogenated in the presence of 0.5 g of 10%Pd/C at 50 psi for 1 hour. The solution was filtered and the solventremoved in vacuo. The residue was partitioned between 10% aqueous sodiumcarbonate solution and ethyl acetate. The organic phase was washed withwater, saturated aqueous sodium chloride solution dried over magnesiumsulfate and concentrated in vacuo to afford 9.8 g of the title compoundas an oil.

Step D'

Methyl (S)-(4-fluorophenyl)glycinate

A solution of 58.4 g of methyl (±) 4-(fluorophenyl)glycinate (from StepC') in 110 ml of 7:1 v/v ethanol/water was mixed with a solution of 28.6g (0.0799 mol) of O,O'-(+)-dibenzoyltartaric acid ((+)-DBT) (28.6 g,0.0799 mol) in 110 ml of 7:1 v/v ethanol:water and the resultingsolution was allowed to age at room temperature. Ethyl acetate (220 ml)was added after crystallisation was complete and the resulting mixturewas cooled to -20° C. and filtered to afford 32.4 g of methyl(S)-(4-fluorophenyl)glycinate, (+)-DBT salt (ee=93.2%). The motherliquors were concentrated in vacuo and the free base was liberated bypartitioning between ethyl acetate and aqueous sodium carbonatesolution. A solution of free base, so obtained, in 110 ml of 7:1 v/vethanol/water was mixed with a solution of 28.6 g (0.0799 mol) ofO,O'-(-)-dibenzoyltartaric acid ((-)-DBT) (28.6 g, 0.0799 mol) in 110 mlof 7:1 v/v ethanol:water and the resulting solution was allowed to ageat room temperature. Ethyl acetate (220 ml) was added aftercrysallisation was complete and the resulting mixture was cooled to -20°C. and filtered to afford 47.0 g of methyl(R)-(4-fluorophenyl)glycinate, (-)-DBT salt (ee=75.8%). Recycling of themother liquors and addition of (+)-DBT gave a second crop of 7.4 g of(S)-(4-fluorophenyl)glycinate, (+)-DBT salt (ee=96.4%). The two crops ofthe (S)-amino ester (39.8 g) were combined in 200 ml of 7:1 v/vethanol/water, heated for 30 minutes and cooled to room temperature.Addition of ethyl acetate, cooling, and filtration afforded 31.7 g of(S)-(4-fluorophenyl)glycinate, (+)-DBT salt (ee>98%). Enantiomericexcess was determined by chiral HPLC (Crownpak CR(+) 5% MeOH in aq HClO₄pH2 1.5 ml/min 40° C. 200 nm).

A mixture of 17.5 g of (S)-(4-fluorophenyl)glycinate, (+)-DBT salt and32 ml of 5.5N HCl (32 ml) was heated at reflux for 1.5 hours. Thereaction mixture was concentrated in vacuo and the residue was dissolvedin 40 ml of water. The aqueous solution was washed (3×30 ml of ethylacetate) and the layers were separated. The pH of the aqueous layer wasadjusted to 7 using ammonium hydroxide and the precipitated solid wasfiltered to afford 7.4 g of the title compound (ee=98.8%).

DESCRIPTION 2 4-Benzyl-3-(S)- (4-fluorophenyl)-2-morpholinone

Step A

N-Benzyl-(S)-(4-fluorophenyl)glycine

A solution of 1.87 g (11.05 mmol) of (S)-(4-fluorophenyl)-glycine (fromDescription 1) and 1.12 ml (11.1 mmol) of benzaldehyde in 11.1 ml of 1Naqueous sodium hydroxide solution and 11 ml of methanol at 0° C. wastreated with 165 mg (4.4 mmol) of sodium borohydride. The cooling bathwas removed and the resulting mixture was stirred at room temperaturefor 30 minutes. Second portions of benzaldehyde (1.12 ml (11.1 mmol))and sodium borohydride (165 mg (4.4 mmol) were added to the reactionmixture and stirring was continued for 1.5 hours. The reaction mixturewas partitioned between 100 ml of ether and 50 ml of water and thelayers were separated. The aqueous layer was separated and filtered toremove a small amount of insoluble material. The filtrate was acidifiedto pH 5 with 2N aqueous hydrochloric acid solution and the solid thathad precipitated was filtered, rinsed well with water, then ether, anddried to afford 1.95 g of the title compound. ¹ H NMR (400 MHz, D₂O+NaOD) δ3.33 (2H, AB q, J=8.4 Hz), 3.85 (1H, s), 6.79-7.16 (4H, m).

Step B

4-Benzyl-3-(S)-(4-fluorophenyl)-2-moropholinone

A mixture of 1.95 g (7.5 mmol) of N-benzyl (S)-(4-fluorophenyl) glycine,3.90 ml (22.5 mmol) of N,N-diisopropyl-ethylamine, 6.50 ml (75.0 mmol)of 1,2-dibromoethane and 40 ml of N,N-dimethylformamide was stirred at100° C. for 20 hours (dissolution of all solids occurred on warming).The reaction mixture was cooled and concentrated in vacuo. The residuewas partitioned between 250 ml of ether and 100 ml of 0.5N potassiumhydrogen sulfate solution and the layers were separated. The organiclayer was washed with 100 ml of saturated aqueous sodium bicarbonatesolution, 3×150 ml of water, dried over magnesium sulfate, andconcentrated in vacuo. Flash chromatography on 125 g of silica gel using3:1 v/v hexanes/ether as the eluant afforded 1.58 g (74%) of the titlecompound as an oil. ¹ H NMR (400 MHz, CDCl₃) δ2.65 (1H, dt, J=3.2, 12.8Hz), 3.00 (1H, dt, J=12.8, 2.8 Hz), 3.16 (1H, d, J=13.6 Hz), 3.76 (1H,d, J=13.6 Hz), 4.24 (1H, s), 4.37 (1H, dt, J=13.2, 3.2 Hz), 4.54 (1H,dt, J=2.8, 13.2 Hz), 7.07-7.56 (9H, m).

DESCRIPTION 3 4-Benzyl-2 -(R)-(3,5-bis(trifluoromethyl)benzoyloxy)-3-(S)-(4-fluorophenyl)morpholine

A solution of 2.67 g (10.0 mmol) of4-benzyl-3-(S)-(4-fluorophenyl)-2-morpholinone (Description 2) in 40 mlof dry THF was cooled to -78° C. The cold solution was treated with 12.5ml of 1.0M L-Selectride® solution in THF, maintaining the internalreaction temperature below -70° C. The resulting solution was stirredcold for 45 minutes and the reaction was charged with 3.60 ml(20.0 mmol)of 3,5-bis(trifluoromethyl)benzoyl chloride. The resulting yellowmixture was stirred cold for 30 minutes and the reaction was quenchedwith 50 ml of saturated aqueous sodium bicarbonate solution. Thequenched mixture was partitioned between 300 ml of ether and 50 ml ofwater and the layers were separated. The organic layer was dried overmagnesium sulfate. The aqueous layer was extracted with 300 ml of ether;the extract was dried and combined with the original organic layer. Thecombined organics were concentrated in vacuo. Flash chromatography on150 g of silica gel using 37:3 v/v hexanes/ether as the eluant afforded4.06 g (80%) of the title compound as a solid. ¹ H NMR (200 MHz, CDCl₃)δ2.50 (1H, dt, J=3.4, 12.0 Hz), 2.97 (1H, app d, J=12.0 Hz), 2.99 (1H,d, J=13.6 Hz), 3.72-3.79 (1H, m), 3.82 (1H, d, J=2.6 Hz), 4.00 (1H, d,J=13.6 Hz), 4.20 (dt, J=2.4, 11.6 Hz), 6.22 (1H, d, J=2.6 Hz), 7.22-7.37(7H, m), 7.57 (2H, app d, J=6.8 Hz), 8.07 (1H, s), 8.47 (2H, s). MS(FAB) m/z 528 (M+H, 25%), 270 (100%). Analysis Calcd. for C₂₆ H₂₀ F₇ NO₃: C, 59.21; H, 3.82; N, 2.66; F, 25.21. Found: C, 59.06; H, 4.05; N,2.50; F, 25.18%

DESCRIPTION 44-Benzyl-2-(R)-(1-(3,5-bis(trifluoromethyl)ethenyl)ethenyloxy)-3-(S)-(4-fluorophenyl)morpholine

Step A

Dimethyl titanocene

A solution of 2.49 g (10.0 mmol) of titanocene dichloride in 50 ml ofether in the dark at 0° C. was treated with 17.5 ml of 1.4Mmethyllithium solution in ether maintaining the internal temperaturebelow 5° C. The resulting yellow/orange mixture was stirred at roomtemperature for 30 minutes and the reaction was quenched by slowlyadding 25 g of ice. The quenched reaction mixture was diluted with 50 mlof ether and 25 ml of water and the layers were separated. The organiclayer was dried over magnesium sulfate and concentrated in vacuo toafford 2.03 g (98%) of the title compound as a light-sensitive solid.The dimethyl titanocene could be stored as a solution in toluene at 0°C. for at least 2 weeks without apparent chemical degradation. ¹ H NMR(200 MHz, CDCl₃) δ-0.15 (6H, s), 6.06 (10H, s).

Step B

4-Benzyl-2-(R)-(1-(3,5-bis(trifluoromethyl)phenyl)ethenyloxy)-3-(S)-(4-fluorophenyl)morpholine

A solution of the compound of Description 3 (2.50 g, 4.9 mmol) and 2.50g (12.0 mmol) of dimethyl titanocene (from Step A) in 35 ml of 11 v/vTHF/toluene was stirred in an oil bath at 80° C. for 16 hours. Thereaction mixture was cooled and concentrated in vacuo. Flashchromatography on 150 g of silica gel using 3:1 v/v hexanes/methylenechloride as the eluant afforded 1.71 g (69%) of the title compound as asolid. An analytical sample was obtained via recrystallisation fromisopropanol: ¹ H NMR (400 MHz, CDCl₃) δ2.42 (1H, dt, J=3.6, 12.0 Hz),2.90 (1H, app d, J=12.0 Hz), 2.91 (1H, d, J=13.6 Hz), 3.62-3.66 (1H, m),3.72 (1H, d, J=2.6 Hz), 3.94 (1H, d, J=13.6 Hz), 4.09 (1H, dt, J=2.4,12.0 Hz), 4.75 (1H, d, J=3.2 Hz), 4.82 (1H, d, J=3.2 Hz), 5.32 (1H, d,J=2.6 Hz), 7.09 (2H, t, J=8.8 Hz), 7.24-7.33 (5H, m), 7.58-7.62 (2H, m),7.80 (1H, s), 7.90 (2H, s); MS (FAB) 526 (M+H, 75%), 270 (100%).Analysis Calcd. for C₂₇ H₂₂ F₇ NO₂ : C, 61.72; H, 4.22; N, 2.67; F,25.31. Found: C, 61.79; H, 4.10; N, 2.65; F, 25.27%

DESCRIPTION 52-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine

The compound of Description 4 (4.0 g) was dissolved in ethyl acetate (50ml) and isopropanol (16 ml). To this solution was added palladium oncharcoal (1.5 g) and the mixture was hydrogenated at 40 psi for 36 h.The catalyst was removed by filtration through Celite and the solventswere removed in vacuo. The residue was purified by flash chromatographyon silica using 100% ethyl acetate and then 1-10% methanol in ethylacetate. This afforded isomer A 500mg (15%) and isomer B 2.6 g (80%) asclear oils - isomer B crystallised on standing. For the title compound:¹ H NMR (400 MHz, CDCl₃) δ1.16 (3H, d, J=6.8 Hz), 1.80 (1H, br s), 3.13(1H, dd, J=3.2, 12.4 Hz), 3.23 (1H, dt, J=3.6, 12.4 Hz), 3.63 (1H, dd,J=2.4, 11.2 Hz), 4.01 (1H, d, J=2.4 Hz), 4.13 (1H, dt, J=3.2, 12.0 Hz),4.42 (1H, d, J=2.4 Hz), 4.19 (1H, q, J=6.8 Hz), 7.04-7.09 (2H, m),7.27-7.40 (4H, m), 7.73 (1H, s); MS (FAB) 438 (M+H, 75%), 180 (100%).

EXAMPLE 12-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(1,24-triazol-3-yl)methylmorpholine

A solution of the compound of Description 5 (3.77 g) and potassiumcarbonate (3.59 g) in dry dimethylformamide (7 ml) was stirred at roomtemperature for 10 min. N-Formyl-2-chloroacetamidrazone (preparedaccording to Yanagisawa I., J. Med Chem. 71. 1984, 27, 849) was addedand the reaction mixture was heated at 60° C. for 1 hour. Thetemperature was then increased to 140° C. for 2 h. The mixture wascooled and partitioned between ethyl acetate and water and the organicphase was washed with water, brine, dried (MgSO₄) and evaporated to givea brown oil. The residue was purified by chromatography on silica using1-5% methanol in dichloromethane. This afforded the product as a whitefoam (2.99 g). ¹ H NMR (360 MHz, DMSO) δ8.25 (1H, s), 7.85 (1H, s), 7.50(2H, t), 7.37 (2H, s), 7.11 (2H, t, J=9.0 Hz), 4.93 (1H, q, J=6.6 Hz),4.32 (1H, d, J=2.8 Hz), 4.09 (1H, dt, J=11.5 Hz), 3.63 (1H, d, J=14.1Hz), 3.59 (1H, d, J=3.0 Hz), 3.17 (1H, d, J=14.0 Hz), 2.49 (1H, dt,J=15.7 Hz), 1.36 (3H, d, J=6.6 Hz). MS (CI⁺) m/z 519. Analysis Calcd.for C₂₃ H₁₉ F₇ N₄ O₂ : C, 53.29; H, 4.08; N, 10.81; Found: C, 52.92; H,3.94; N, 10.33%

EXAMPLE 2 2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(1,3-imidazol-4-yl)methylmorpholine

Step A

4-Hydroxymethyl-N-(ρ-toluenesulfonyl)imidazole

4-Hydroxymethylimidazole hydrochloride (10 g) was suspended indichloromethane (200 ml). ρ-Toluenesulfonyl chloride (15.58 g) was addedand triethylamine (25.8 ml) was added dropwise to the stirred reactionmixture which was allowed to stir at room temperature overnight. Themixture was washed with water (2×100 ml) and brine (1×100 ml) and theorganic layer was dried and evaporated to leave a clear oil which wasrecrystallised from ethyl acetate/hexane to afford a white crystallinesolid (15 g, 80%). ¹ H NMR (360 MHz, CDCl₃) δ2.44 (3H, s), 4.55 (2H, s),7.21 (1H, s), 7.35 (2H, d, J=8.0 Hz), 7.62 (2H, d, J=8.0 Hz), 7.98 (1H,s). MS (CI⁺) m/z 253 (M+H, 100%).

Step B

(N-P-Toluenesulfonyl)imidazol-2 -yl)methyl methanesulfonate

The alcohol described in (a) above (1 g) was dissolved indichloromethane (15 ml) and the solution was cooled in an ice-methanolbath. Triethylamine (0.4 g) was added dropwise in dichloromethane (1 ml)followed by methanesulfonyl chloride (0.45 g). The mixture was washedwith water (2×10 ml) and brine (1×10 ml) and the organic layer was driedand evaporated to leave a white crystalline powder (1.3 g). This wasused in the next reaction without further purification. ¹ H NMR (360MHz, CDCl₃) δ2.45 (3H, s), 3.00 (3H, s), 5.13 (2H, s), 7.39 (2H, d,J=8.0 Hz), 7.40 (1H, s), 7.84 (2H, d, J=8.0 Hz), 8.00 (1H, s). MS (CI⁺)m/z 267 ((M-CH₃ O)⁺, 30%).

Step C

2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-5fluorophenyl)-4-(N-p-toluenesulfonyl- 1,3-imidazol-4-yl)methylmorpholine

The compound of Description 5 (500 mg), potassium carbonate (474 mg) andthe mesylate referred to in (b) above (432 mg) were suspended inN,N-dimethylformamide (5 ml) and the resulting mixture was stirred at60° C. for 4 hr. The mixture was cooled and diluted with water (50 ml).The 10 mixture was extracted with ethyl acetate (3×20 ml) and theorganic layer was washed with brine, dried (MgSO₄) and evaporated. Theresidue was purified by column chromatography on silica using 30% ethylacetate in petrol as eluant to afford the product (515 mg, 70%) as awhite crystalline solid. MS (CI⁺) m/z 672 ((M+H)⁺, 100%).

Step D

2-(R)-(1-(R)-(3,5-Bis(trifluoromethylphenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(1,3-imidazol-4-yl)methylmorpholine

The compound referred to in (c) above (500 mg) was deprotected bytreatment with ethereal hydrogen chloride. The mixture was evaporated invacuo and the residue was triturated with ether several times and theethereal washings were decanted to remove the liberatedp-toluenesulfonyl chloride. The residual product was treated withaqueous potassium carbonate to liberate the free base and this wasextracted with ethyl acetate. The organic layer was washed with water,brine, dried (MgSO₄) and evaporated in vacuo. The residue was purifiedby column chromatography on silica using 2-6% methanol indichloromethane as eluant. ¹ H NMR (250 MHz, CDCl₃) δ1.45 (3H, d, J=7.0Hz), 2.55 (1H, dt, J=12.0, 3.0 Hz), 2.96 (1H, d, J=12.0 Hz), 3.18 (1H,d, J=14.0 Hz), 3.41 (1H, d, J=3.0 Hz), 3.67 (1H, m), 3.71 (1H, d, J=14.0Hz), 4.25 (1H, m), 4.31 (1H, d, J=3.0 Hz), 4.86 (1H, q, J=7.0 Hz), 6.81(1H, s), 7.05 (2H, t, J=8.0 Hz), 7.13 (2H, s), 7.42 (2H, br s), 7.63(1H, s), 7.68 (1H, s). MS (CI⁺) m/z 518 ((M+H)⁺, 20%).

The following examples illustrate pharmaceutical compositions accordingto the invention.

EXAMPLE 3A

Tablets containing 1-25 mg of compound

    ______________________________________                                                      Amount mg                                                       ______________________________________                                        Compound of formula (I)                                                                       1.0        2.0    25.0                                        Microcrystalline cellulose                                                                    20.0       20.0   20.0                                        Modified food corn starch                                                                     20.0       20.0   20.0                                        Lactose         58.5       57.5   34.5                                        Magnesium Stearate                                                                            0.5        0.5    0.5                                         ______________________________________                                    

EXAMPLE 3B

Tablets containing 26-100 mg of compound

    ______________________________________                                                      Amount mg                                                       ______________________________________                                        Compound of formula (I)                                                                       26.0       50.0   100.0                                       Microcrystalline cellulose                                                                    80.0       80.0   80.0                                        Modified food corn starch                                                                     80.0       80.0   80.0                                        Lactose         213.5      189.5  139.5                                       Magnesium Stearate                                                                            0.5        0.5    0.5                                         ______________________________________                                    

The compound of formula (I), cellulose, lactose and a portion of thecorn starch are mixed and granulated with 10% corn starch paste. Theresulting granulation is sieved, dried and blended with the remainder ofthe corn starch and the magnesium stearate. The resulting granulation isthen compressed into tablets containing 1.0 mg, 2.0 mg, 25.0 mg, 26.0mg, 50.0 mg and 100 mg of the active compound per tablet.

EXAMPLE 4

Parenteral injection

    ______________________________________                                                            Amount mg                                                 ______________________________________                                        Compound of formula (I)                                                                             1 to 100 mg                                             Citric Acid Monohydrate                                                                             0.75 mg                                                 Sodium Phosphate      4.5 mg                                                  Sodium Chloride       9 mg                                                    Water for injection   to 10 ml                                                ______________________________________                                    

The sodium phosphate, citric acid monohydrate and sodium chloride aredissolved in a portion of the water. The compound of formula (I) isdissolved or suspended in the solution and made up to volume.

EXAMPLE 5

Topical formulation

    ______________________________________                                                            Amount mg                                                 ______________________________________                                        Compound of formula (I)                                                                             1-10 g                                                  Emulsifying Wax       30 g                                                    Liquid paraffin       20 g                                                    White Soft Paraffin   to 100 g                                                ______________________________________                                    

The white soft paraffin is heated until molten. The liquid paraffin andemulsifying wax are incorporated and stirred until dissolved. Thecompound of formula (I) is added and stirring continued until dispersed.The mixture is then cooled until solid.

EXAMPLE 6A

(Surface-Active Agent) Injection Formulation

    ______________________________________                                        Compound of formula (I)                                                                             up to 10 mg/kg                                          Tween 80 ™         up to 2.5%                                              ______________________________________                                    

in 5% aqueous mannitol (isotonic)!

The compound of formula (I) is dissolved directly in a solution of thecommercially available Tween 80™ (polyoxyethylenesorbitan monooleate)and 5% aqueous mannitol (isotonic).

EXAMPLE 6B

(Emulsion) Injection Formulation

    ______________________________________                                        Compound of formula (I)                                                                             up to 30 mg/ml                                          Intralipid ™ (10-20%)                                                      ______________________________________                                         The compound of formula (I) is dissolved directly in the commercially         available Intralipid ™ (10 or 20%) to form an emulsion.               

EXAMPLE 6C

Alternative (Emulsion) Injectable Formulation

    ______________________________________                                                             Amount                                                   ______________________________________                                        Compound of formula (I)                                                                              0.1-10 mg                                              Soybean oil            100 mg                                                 Egg phospholipid       6 mg                                                   Glycerol               22 mg                                                  Water for injection    to 1 ml                                                ______________________________________                                    

All materials are sterilized and pyrogen free. The compound of formula(I) is dissolved in soybean oil. An emulsion is then formed by miningthis solution with the egg phospholipid, glycerol and water. Theemulsion is then sealed in sterile vials.

We claim:
 1. A compound of formula (I), or a pharmaceutically acceptablesalt or prodrug thereof: ##STR11## wherein X is N.
 2. The compound:2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(1,2,4-triazol-3-yl)methylmorpholine;ora pharmaceutically acceptable salt or prodrug thereof.
 3. Apharmaceutical composition comprising a compound as claimed in claim 1in association with a pharmaceutically acceptable carrier or excipient.4. A method for the treatment or prevention of physiological disordersassociated with an excess of tachykinins, which method comprisesadministration to a patient in need thereof of a tachykinin reducingamount of a compound according to claim 1, or a pharmaceuticallyacceptable salt or prodrug thereof.
 5. A method according to claim 4 forthe treatment or prevention of pain or inflammation.
 6. A methodaccording to claim 4 for the treatment or prevention of migraine.
 7. Amethod according to claim 4 for the treatment or prevention of emesis.